CHICAGO — Six or more months of continuous androgen deprivation therapy was associated with significantly increased risk of fragility fractures and type 2 diabetes in an observational study of nearly 20,000 men aged 66 years and older with prostate cancer, reported investigators at the annual meeting of the American Society of Clinical Oncology.
Continuous androgen deprivation was not associated with elevated risk for either acute myocardial infarction or hypercholesterolemia, however. There was actually a slight decrease in risk for dyslipidemia, and nonsignificant trends toward lower rates of AMI and sudden cardiac death, said Dr. Shabbir M.H. Alibhai.
Concern about adverse effects of androgen deprivation therapy on bone is based on four retrospective studies and a case-control study showing an increase risk for both fragility fractures and nonfragility fractures with its use, according to Dr. Alibhai, a research scientist in the department of medicine at Princess Margaret Hospital and the University of Toronto.
A large prospective study by Dr. Nancy L. Keating and her coauthors at Brigham and Women's Hospital in Boston showed use of a gonadotropin-releasing hormone agonist was associated with a 44% increased risk of incident diabetes, 16% increase each in risk of coronary heart disease and sudden cardiac death, and an 11% rise in risk of MI (J. Clin. Oncol. 2006 20;24:4448–56).
“These findings are worrisome, but at the same time, there are some limitations that must be kept in mind,” said Dr. Alibhai. “The findings are not entirely consistent among studies. Some studies suggested, for example, increased rate of fatal myocardial infarction, but no overall increased rate of myocardial infarction. And another study suggested that while androgen deprivation increased the risk of MI, diabetes, and hypertension, paradoxically, it did not seem to in that cohort.”
Dr. Alibhai and his colleagues looked at data on 19,709 men in Ontario (Canada), who had continuous androgen deprivation therapy for at least 6 months or had undergone bilateral orchiectomy, and an identical number of controls. The treated patients were matched by age and prior prostate cancer therapy to other men who did not receive androgen deprivation.
The primary end points were fragility fractures, incident diabetes, incident dyslipidemia, acute MI, and sudden cardiac death. Secondary outcomes were any fracture, heart failure, stroke, use of diagnostic cardiac catheterization, and cardiac revascularization with either angioplasty or coronary artery bypass graft surgery.
The investigators found in a time-to-event analysis that after a mean of 6.47 years, use of androgen deprivation was associated with a hazard ratio for fragility fractures of 1.65 (P less than .001), and a 1.26 hazard ratio for incident diabetes (P less than .001).
In contrast, there was a 14% lower risk for incident dyslipidemia (HR 0.86, P less than .001), and nonsignificant trends toward lower MI risk (HR 0.92, P = .059) and time to sudden cardiac death (HR 0.96, P = .53).
In analysis of secondary outcomes, androgen deprivation was significantly associated with higher risk of any fracture (HR 1.46) and lower risk for stroke (HR 0.88), cardiac catheterization (HR 0.88), and cardiac revascularization (HR 0.87).
Dr. Alibhai acknowledged that the study was limited by its restriction to men 66 years and older, possible undercoding of some comorbidities or minor fractures, lack of information on tumor stage or grade, the fact that the outcomes of dyslipidemia were not validated, and that propensity analysis lessens but does not eliminate the potential for confounding.
“In men who are age 66 [years] or older, on continuous androgen deprivation for at least 6 months,” Dr. Alibhai said in his conclusion, “this therapy was associated with an increased risk of fragility fracture—of course as well as any fracture—a decreased risk of dyslipidemia … and no appreciable impact on myocardial infarction. And, if anything, there was a slight decrease in acute myocardial infarction in this cohort, which goes against the previously published studies to date.”
The study was supported by the Toronto General and Toronto Western Hospital Foundation and the National Cancer Institute of Canada. Dr. Alibhai reported no financial conflict of interest.